1. Field of the Invention
Compounds and methods related to derivatives of pivagabine for the treatment of central nervous system disorders.
2. Description of the Related Art
Pivagabine, or 4-[(2,2-dimethyl-1-oxopropyl)amino]butanoic acid:

is a hydrophobic derivative of GABA which can cross the haemato-encephalic barrier and act as an active pharmaceutical compound against hypertension and cerebral disturbances, such as epilepsy. Pivagabine has been found to be substantially free of toxic effects in vivo in mouse and in rat; in fact, LD50 by intravenous route is 1750 mg/kg in the mouse while no toxic effects were observed up to the dose of 1 g/kg by intraperitoneal route in the rat. It shows a certain anti-depressive and anxiolytic activity in the mouse and can be used to treat mood disturbances, anxiety disorders, somatoform disorders and adjustment disorders.
However, pivagabine was originally developed as an analog of GABA with the proposition that it would be hydrolyzed to GABA after entering the brain. ADME (Absorption, Distribution, Metabolism & Excretion) studies suggest that only very low levels of GABA are detected in the brain. Therefore, the mechanism of action of pivagabine is likely not related to GABA. In attempts to elucidate the mechanism of action it was discovered that pivagabine affects the CRF protein content of specific brain regions (hypothalamus and cerebral cortex) particularly during stress conditions (application of foot shock in rodents). This effect is centrally mediated and does not require an intact hypothalamic-pituitary-adrenal axis. Also, in modulating CRF, pivagabine is not acting as a CRF-1 receptor antagonist since it does not reverse the effects of CRF administered directly into the brain of rodents.
Unfortunately, current forms of pivagabine are poorly absorbed by the brain which is the relevant organ for the pharmacologic actions of pivagabine. Thus there is a need to optimize brain levels of pivagabine when administrated by the oral route. Optimized bioavailability of the drug at its site of action is one of the most important aims of the pharmaceutical industry during the development phase of a new product. Bioavailability represents the quantity of a biological agent, i.e. the active component, absorbed from a pharmaceutical formulation that is absorbed into blood and circulated, the rate of this absorption, and the rate of clearance from the body after the drug has been absorbed. This implies that the molecule crosses one or several biological membranes before reaching the site of action, which is the brain in the case of pivagabine. It has been generally considered that the physico-chemical properties of an orally administered drug determine its bioavailability. Among these parameters are the molecular weight (very low permeability is known for therapeutics with molecular weight more than 600 D), the pKa, and the lipophilicity as characterized by the octanol/water partition coefficient (Log D).
In particular, though pivagabine is rapidly absorbed into the blood, the amount of drug that enters the brain is relatively small (the brain concentration of pivagabine is only about 7% that of the blood in rats). Therefore, high doses of the drug (1800 mg/day in humans) have to be administered to achieve the desired behavioral effects. This presents a problem with manufacturing (high volumes have to be produced) and with developing finished formulations (tablets or capsules) that are commercially acceptable. One problem with pivagabine is that its administration has not achieved high enough levels in the central nervous system. The current embodiments address these concerns and provide other advantages as well.